Synthesis of substituted furans

ABSTRACT

A method is provided of preparing a compound of formula II: where: R 1  and R 2  are independently selected from —CH2OR′, —CHO, —COOR′ and —H, provided that R 1  and R 2  are not both —H; and R′ is selected from —H and C 1-6  hydrocarbyl groups, from a compound of formula I: the compounds of formulas I and II being optionally in the form of a salt. The method comprises dehydrating the compound of formula I at: a pH in the range of from 0 to 6 or 8 to 11.5; and a temperature in the range of from 10 to 80° C. The method is particularly useful for synthesizing substituted furans from compounds derived from sugars.

The present disclosure relates to methods for synthesizing substitutedfurans, in particular to methods for synthesizing furans from compoundsderived from sugars.

BACKGROUND OF THE DISCLOSURE

Substituted furans are a class of compounds of significant interest,since they can be derived from renewable resources such as sugars andare useful in a wide range of applications. Substituted furans areuseful in the preparation of polymers. 2,5-Furandicarboxylic acid (FDCA)is particularly useful, as it represents a renewable monomer which canbe used in polymers instead of terephthalic acid. Moreover, polymerssuch as polyethylene 2,5-furandicarboxylate (PEF) which contain FDCA canexhibit improved properties as compared to the equivalentterephthalate-containing polymer.

However, producing substituted furans such as FDCA from renewablesources has been challenging. In particular, many of the steps involvedin converting sugars to substituted furans exhibit low selectivity andtherefore low yield. Moreover, some methods require the use of fructoseas a starting material, rather than more readily obtainable sugars suchas glucose. Though some methods use glucose, it is often processed intofructose, which can be inefficient.

Recently, there have been a number of advances in the production ofsubstituted furans. For example, a method is disclosed in US 2017/050944in which gluconic acid derivatives are chemically dehydrated in thepresence of a dehydration catalyst to give FDCA. A further method isdisclosed in US 2018/057897 in which 5-hydroxymethyl furoic acid, asubstituted furan, is prepared from 2-keto-3-deoxy-gluconate (KDG).

Though the recent developments are promising, the relatively hightemperatures and high acid concentration required lead to relativelymodest yields with significant quantities of byproduct. Such methods canfurthermore only deliver higher yields when the dehydration is performedin a solvent system which is not fully aqueous, e.g. in an acetic acid-or ethanol-based system, which increases the economic cost of theprocess. Where predominantly aqueous systems have been used, a low yieldis obtained.

Accordingly, there is a need for further methods for preparingsubstituted furans which preferably address one or more of the drawbacksassociated with existing preparation methods.

SUMMARY OF THE DISCLOSURE

The present disclosure provides a method of preparing a compound offormula II:

-   where: R₁ and R₂ are independently selected from —CH₂OR′, —CHO,    —COOR′ and —H, provided that R₁ and R₂ are not both —H; and    -   R′ is selected from —H and C₁₋₆ hydrocarbyl groups,-   from a compound of formula I:

the compounds of formulas I and II being optionally in the form of asalt. The method comprises dehydrating the compound of formula I at a pHin the range of from 0 to 6 or 8 to 11.5; and a temperature in the rangeof from 10 to 80° C.

It has surprisingly been found that compounds of formula I representuseful materials for preparing substituted furans. In particular, theymay be used in methods in which relatively mild conditions are employed,yet which may deliver high levels of conversion and selectivity forsubstituted furans of formula II in a short space of time.

Also provided is a method of preparing a compound of formula III:

-   -   where: R₄ is selected from —OH and —R′;        the compound of formula III being optionally in the form of a        salt. The method comprises preparing a compound of formula II        using a method as defined herein; and, provided that the        compounds of formula II and III do not have the same structure,        converting the compound of formula II into a compound of formula        III.

The present disclosure further provides a method of preparing a polymercomprising a polymeric unit of formula IV:

The method comprises preparing a compound of formula III or a saltthereof using a method as defined herein; and forming the polymer bycarrying out a polymerisation reaction using the compound of formulaIII.

Also provided is a compound of formula I:

-   where: R₁ and R₂ are independently selected from —CH₂OR′, —CHO,    —COOR′ and —H, provided that R₁ and R₂ are not both —H; and    -   R′ is selected from —H and C₁₋₆ hydrocarbyl groups,-   the compound of formula I being optionally in the form of a salt.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the yield obtained when a compound of formulaI is dehydrated to form a compound of formula II under mild conditionsbut at varying pH levels;

FIG. 2 is a graph showing the yield obtained at different time pointsduring the conversion of a compound of formula I into a compound offormula II under mild conditions; and

FIG. 3 is a graph showing the yield obtained when2-keto-3-deoxygluconate, which is not a compound of formula I, isdehydrated under mild conditions but at varying pH levels to give acompound of formula II.

DETAILED DESCRIPTION

The present disclosure provides a method of preparing a compound offormula II from a compound of formula I. Thus, the method involvesperforming the following dehydration reaction:

It will be appreciated that a molecule of water is lost from eachmolecule of the compound of formula I as it converts to a compound offormula II.

Dehydration Reaction Conditions

The method of the present disclosure involves dehydrating the compoundof formula I under relatively mild conditions. Specifically, thedehydration reaction is carried out at a pH in the range of from 0 to 6or 8 to 11.5, and a temperature in the range of from 10 to 80° C.

The dehydration reaction may be carried out at a temperature of up to70° C., preferably up to 55° C., and more preferably up to 50° C. Thedehydration reaction may be carried out at a temperature of at least 15°C., preferably at least 20° C., and more preferably at least 25° C.Thus, the dehydration reaction may be carried out a temperature of from15 to 70° C., preferably from 20 to 55° C., and more preferably from 25to 50° C.

In some instances, the dehydration reaction is carried out under acidicconditions. For instance, the dehydration reaction may be carried out ata pH of up to 5, preferably up to 4, and more preferably up to 3.5. Thedehydration reaction may be carried out at a pH of at least 1.5,preferably at least 1.75, and more preferably at least 2. Thus, thedehydration reaction may be carried out at a pH of from 1.5 to 5,preferably from 1.75 to 4, and more preferably from 2 to 3.5.

In other instances, the dehydration reaction is carried out under basicconditions. For instance, the dehydration reaction may be carried out ata pH of at least 8.5, preferably at least 9, and more preferably atleast 9.5. The dehydration reaction may be carried out at a pH of up to11.5, preferably up to 11, and more preferably up to 10.5. Thus, thedehydration reaction may be carried out at a pH of from 8.5 to 11.5,preferably from 9 to 11, and more preferably from 9.5 to 10.5.

pH may be measured using conventional methods, e.g. using a pH probe,under the conditions of the reaction.

A suitable pH may be imparted on the reaction mixture by virtue of theR₁ and R₂ groups in the compound of formula I, for instance if R₁ and/orR₂ are acidic groups such as —COOH or basic groups such as —COO— wherethe compound of formula I is present in the form of a salt.

However, at least one of an acid, base or buffer will typically be addedto the reaction mixture to adjust the pH. A buffer will generally beused, optionally with an additional acid or base.

The acid and base will typically catalyse the reaction, i.e. they willnot be consumed during the course of the reaction.

A wide range of acids may be used. For instance, the acid may beselected from organic acids, such as from C₁₋₆ carboxylic acids. Theacid may be selected from inorganic acids, such as from hydrochloricacid, sulfuric acid, phosphoric acid, nitric acid and hydrobromic acid.

In some embodiments, an acid may be used in the form of a solid. Thus,the reaction may be carried out using a heterogeneous, and preferablysolid-phase, catalyst.

A wide range of bases may be used. For instance, the base may beselected from nitrogen-containing bases such as ammonia, an amine (e.g.a primary, secondary or tertiary, and preferably tertiary amine) andnitrogen-containing heterocycles (e.g. pyridine, imidazole, piperidineor piperazine). The base may be selected from metal-containing basessuch as metal hydroxides (e.g. alkali or alkaline earth metalhydroxides), metal oxides (e.g. transition metal oxides) or metalcarbonates (e.g. alkali or alkaline earth metal carbonates orhydrogencarbonates).

As with the acid, in some embodiments, a base may be used in the form ofa solid.

A wide range of buffers may be used. For instance, the buffer may beselected from a citrate buffer, a formate buffer, an acetate buffer, acarbonate buffer, a phosphate buffer, anN-cyclohexyl-2-aminoethanesulfonic acid (CHES) buffer, a borate buffer,a citrate-phosphate buffer, a2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES) buffer,a tris(hydroxymethyl)-aminomethane (Tris) buffer, a2-(N-morpholino)ethanesulfonic acid (MES) buffer, a sugar acid buffer,or an ammonia buffer.

The pH will typically remain fairly constant during the reaction,particularly where a buffer is used. However, it may be desirable tomonitor and, where necessary, adjust the pH (e.g. so that it remainswith a range of 0.8, and preferably ±0.5 of the target pH) during thecourse of the dehydration reaction, for instance where the reaction iscarried out in a continuous mode.

The dehydration reaction may be carried out in the presence of a proticsolvent, such as water. Preferably, the solvent system in which thereaction is carried out contains water in an amount of at least 50%,preferably at least 70%, and more preferably at least 90% by volume. Insome instances, the solvent system consists substantially of water.

The compound of formula I may be added to the reactor in an amount ofgreater than 5 g/L, preferably greater than 10 g/L, and more preferablygreater than 20 g/L of solvent. However, in some embodiments, e.g. wherea one-pot synthesis is carried out in which the compound of formula I isprepared from a sugar acid in the same reactor as the compound offormula II (this is described in greater detail below), theconcentration of the compound of formula I may be low. In theseinstances, the compound of formula I may be present in the reactor in anamount of greater than 0.1 g/L, preferably greater than 0.2 g/L, andmore preferably greater than 0.5 g/L. Where compounds of formula I arepresent in the form of a salt, these values represent the amount of thecorresponding salt-free form (e.g. if the compound of formula I containsthe group —COOLi, then the corresponding salt-free form would containthe group —COOH).

The dehydration reaction will generally be conducted at ambientpressure, i.e. without the application or removal of pressure. Thus, thedehydration reaction may take place at a pressure of about 1 atm, e.g.from 0.95 to 1.05 atm. However, higher pressures may also be used.

The dehydration reaction will usually take place under agitatedconditions, e.g. under stirring.

An advantage of the present invention is that the dehydration reactiontakes place very quickly and at high yield.

In some instances, the dehydration reaction may be carried out as abatch process. A batch process may be carried out for a period of up to336 hours, preferably up to 168 hours, more preferably up to 72 hours.Since the dehydration reaction takes place quickly, in some instances,and even on an industrial scale, the batch process may be carried outfor a period of up to 24 hours or even less, e.g. for a period of up to12 hours. Batch processes will be carried out in a batch reactor system.

However, the dehydration reaction will preferably be carried out as acontinuous process. A continuous process may be carried out for at least14 days, preferably at least 30 days, and more preferably at least 60days. Continuous processes will be carried out in a continuous reactorsystem.

A further advantage is that minimal byproducts are formed, even where aone-pot synthesis is carried out in which the compound of formula I isprepared from a sugar-acid in the same reactor as the compound offormula II (this is described in greater detail below).

The dehydration reaction is preferably carried out on an industrialscale. Thus, the dehydration reaction may be carried out in a reactorhaving a volume of greater than 100 L, preferably greater than 500 L,and more preferably greater than 1000 L.

The compound of formula II may be produced in an amount of greater than5 g/L, preferably greater than 10 g/L, and more preferably greater than20 g/L of solvent.

The compounds of formula II may be obtained in a yield of at least 60%,preferably at least 80%, preferably at least 90%, preferably at least95%, preferably at least 99%, and more preferably at least 99.5% yieldfrom formula I.

Compounds

Compounds of formula I and II are shown below:

It will be appreciated that groups present as R₁ and R₂ in the compoundsof formula I will not be modified during the course of the dehydrationreaction, i.e. R₁ and R₂ are the same in compounds of formula I andformula II.

R₁ and R₂ are independently selected from —CH₂OR′, —CHO, —COOR′ and —H.R₁ and R₂ are not both —H or, in other words, the compounds of formula Iand II must be substituted.

R′ is selected from H and C₁₋₆ hydrocarbyl groups. Preferably, R′ isselected from —H and C₁₋₄ hydrocarbyl groups, more preferably from —Hand C₂₋₃ hydrocarbyl groups, and most preferably is —H. The hydrocarbylgroup is preferably an alkyl group, though other groups such as alkenylgroups may be present.

R₁ and R₂ are preferably selected from —CH₂OH, —CHO, —COOH and —H, andmore preferably from —CH₂OH, —CHO, —COOH.

At least one of R₁ and R₂ may be selected from —COOH.

At least one of R₁ and R₂ may be selected from —CH₂OH.

Preferably, one of R₁ and R₂ is selected from —CH₂OH and the other isselected from —COOH, and more preferably R₁ is —CH₂OH and R₂ is —COOH.Thus, the compound of formula I preferably has the structure:

This structure is particularly preferred, since it is derived from2-keto-3-deoxygluconate which, in turn, may be derived from glucose.This preferred structure gives a compound of formula II which is5-hydroxymethyl-2-furoic acid:

In other embodiments, both R₁ and R₂ are selected from —COOH. Theseembodiments advantageously allow the compound of formula II to be useddirectly in a polymerization reaction.

The compounds of formula I and II may be in the form of a salt.Preferred salts may be selected from alkali metal salts (e.g. lithium,sodium or potassium salts) and alkaline earth metal salts (e.g.magnesium or calcium salts). Carboxyl (—COOH) groups are particularlysuitable for forming salts. A compound of formula II may be in the samesalt form as the compound of formula I.

Preparing Compounds of Formula I

The compounds of formula I may be prepared from a precursor compoundhaving the following formula:

It will be appreciated that precursor I may convert between othertautomeric forms in the reaction mixture, e.g. it may be present in theform of a straight-chain molecule or in the form of a 5- or 6-memberedring. 5- or 6-membered ring forms may include, in addition to the formshown above, 5- or 6-membered lactones where one of R₁ or R₂ is a COOHgroup, and 6-membered pyranose compounds where one of R₁ or R₂represents CH₂OH group.

Thus, the method of the present disclosure may comprise providing thecompound of formula I from precursor I, e.g. by a dehydration reaction:

The dehydration reaction is preferably carried out in the presence of anenzyme, such as a dehydratase.

The compound of formula II may be obtained in a yield of at least 50%,preferably at least 70%, and preferably at least 90% from precursor I.

In some embodiments, a precursor I may be converted into a compound offormula I and, in the same reactor, the compound of formula I convertedinto a compound of formula II. Thus, the reactions may advantageously becarried as a one-pot synthesis, i.e. a synthesis in which anintermediate work-up is not involved.

Where a one-pot synthesis is carried out, though an enzyme may bepresent to promote the conversion of the precursor I to a compound offormula I, the enzyme will typically not be capable of converting thecompound of formula I into a compound of formula II under the reactionconditions of the present disclosure. In these embodiments, it isdesirable to use a pH level which promotes the conversion of a compoundof formula I to a compound of formula II, but which does not reduce theactivity of the enzyme which is, in the same pot, promoting theconversion of precursor I to a compound of formula I. As mentionedabove, in such embodiments, preferred acidic pH levels are from 1.5 to6, preferably from 2 to 6, and more preferably from 3.5 to 6. Preferredbasic pH levels are from 8 to 11.5, preferably from 8 to 10.5, and morepreferably from 8 to 9.5.

In other embodiments, the method of the present disclosure may compriseconverting a precursor I into a compound of formula I, isolating thecompound of formula I, and subsequently converting a compound of formulaI into a compound of formula II.

Preferably, compounds of formula I are obtained from sugar acids. Sugaracids are well-known in the art as monosaccharides which comprise atleast one carboxyl (—COOH) group. Thus, compounds of formula I may beobtained from a precursor I in which at least one of R₁ and R₂, andpreferably R₂, is —COOH.

The method of the present disclosure may further comprise providing thesugar acid from an acid-free sugar. It will be appreciated that, in thecontext of the present disclosure, the term acid-free sugar is intendedto denote monosaccharides which do not contain a —COOH group. Inparticular, the acid sugar may be derived from glucose, e.g. accordingto the following route:

The above route shows oxidation of glucose, followed by dehydration.Alternatively, glucose may be dehydrated and then oxidised, althoughthis is less preferred. Similarly, although the above route shows thepreferred stereochemistry for glucose, any other stereochemistry may bepresent.

The conversion of glucose into an acid sugar is preferably carried outenzymatically, for instance with a first enzyme for the oxidation stepand a second enzyme for the dehydration step. Suitable methods forconverting glucose into 2-keto-3-deoxygluconate are described in US2018/057897, the contents of which is hereby incorporated by reference.

Alternatively, compounds of formula I may be prepared synthetically. Theskilled person would be able to determine suitable methods.

Using Compounds of Formula II

Compounds of formula II may be used in a method of preparing a compoundof formula III:

Thus, according to a further aspect, the present disclosure provides amethod of preparing a compound of formula III. The method comprisespreparing a compound of formula II using a method as defined herein,and, provided that the compounds of formula II and III do not have thesame structure, converting the compound of formula II into a compound offormula III.

Thus, the method comprises carrying out the following reaction:

R₁ and R₂ are as described above.

R₄ is selected from —OH and —R′, where R′ is as described above.Preferably, R₄ is OH.

The compound of formula III may be in the form of a salt. Preferredsalts may be selected from alkali metal salts (e.g. lithium, sodium orpotassium salts) and alkaline earth metal salts (e.g. magnesium orcalcium salts). Carboxyl (—COOH) groups are particularly suitable forforming salts. A compound of formula III may be in the same salt form asthe compound of formula II.

In preferred embodiments, at least one of R₁ and R₂ in formula II isselected from —CH₂OH and —COR′, and the method comprises oxidising thecompound of formula II so as to convert the at least one —CH₂OH and—COR′ group into —COR₄, where R₄ is OH. Suitable oxidation conditionsare known in the art.

In some embodiments, a compound of formula I may be converted into acompound of formula II and, in the same reactor, a compound of formulaII converted into a compound of formula III. Thus, the reactions mayadvantageously be carried as a one-pot synthesis, i.e. a synthesis inwhich an intermediate work-up is not involved.

In alternative embodiments, a compound of formula I may be convertedinto a compound of formula II in a first reactor, and then the compoundof formula II converted into a compound formula III in a second reactor.In these embodiments, the compound of formula II may be extracted and/orpurified before it is transferred to the second reactor.

Compounds of formula III represent useful monomers in the preparation ofpolymers. Thus, in another aspect of the present disclosure, a method isprovided of preparing a polymer comprising a polymeric unit of formulaIV:

The method comprises preparing a compound of formula III, or a saltthereof, using a method as defined herein, and forming the polymer bycarrying out a polymerisation reaction using the compound of formulaIII.

Typically, the compound of formula III will be isolated, and optionallypurified, before it is used to prepare a polymeric unit of formula IV.

The present disclosure further provides compounds of formula II,compounds of formula III or polymers comprising a polymeric unit offormula IV which are obtainable using the methods described herein.

The disclosure will now be described with reference to the accompanyingnon-limiting examples.

EXAMPLES Example 1: Dehydration of a Compound of Formula I at Various pHLevels

Experiments were conducted to determine whether compounds of formula Icould be dehydrated to compounds of formula II with a high yield undermild conditions. The following compound of formula I was used:

A 1 mM aqueous solution of the compound of formula I was diluted 20-foldby volume using buffer, water, or 1% formic acid. Aqueous citric acidsolutions (50 mM) were prepared and adjusted with sodium hydroxide togive citrate acid buffers with pH levels of 3, 3.5 and 4. A sodiumphosphate buffer (50 mM) was used to give a pH of 7. Water was used togive a pH of ˜9.5-10. 1% formic acid was used to give a pH of 2.2. Eachreaction mixture was incubated in a 55° C. oven for 18 hours. A sampleof each reaction mixture after said 18 hours of incubation was analysedby LC-MS/MS to determine the concentration of the compound of formulaII, i.e. 5-hydroxymethyl-2-furoic acid (HMFA). FIG. 1 shows the yieldobtained in each reaction.

It can be seen that a very high yield of the compound of formula II wasobtained under acid or basic conditions, whereas a low yield wasobtained at or around neutral pH. Thus, this example demonstrates aviable method of producing the compound of formula II under relativelymild conditions.

Example 2: Dehydration Yield of a Compound of Formula I with Time

Experiments were conducted to determine whether dehydration of acompound of formula I under mild conditions takes place quickly enoughto be industrially viable. The compound of formula I that was used inExample 1 was also used in these experiments, thereby giving HMFA as thecompound of Formula II.

A 10 mM solution of the compound of formula I was diluted with a citratebuffer (50 mM) to give a 2.5 mM solution of the compound of formula Ihaving a pH of 3.5. The resulting reaction mixture was incubated at 35°C. A sample was taken roughly every 1.5 minutes and analysed byLC-MS/MS. The results are shown in FIG. 2.

It can be seen that the compound of formula I dehydrates extremelyquickly under mild conditions, with approximately 50% conversionobserved in just 10 minutes.

Example 3: Dehydration of Other Compounds of Formula I Under MildConditions

Experiments were conducted to determine whether other compounds offormula I could be dehydrated under mild conditions. The followingcompounds were used in the experiments:

Both compounds converted to the corresponding compounds of formula IIunder mild conditions. A temperature as low as 18° C. was even used toquantitatively convert the second compound (i.e. in which R₁ is —CH₂OHand R₂ is H).

Comparative Example: Dehydration of 2-Keto-3-Deoxygluconate Under MildConditions

Experiments were conducted to determine whether 2-keto-3-deoxygluconate(KDG) could be dehydrated under mild conditions to give HMFA, i.e. acompound of formula II, in a good yield.

McIlvaine's buffer was prepared using a combination of 200 mM disodiumhydrogen phosphate and 100 mM citric acid for use in reaction mixtureshaving a pH of 3, 3.5, 4, or 4.5. 100 mM sodium phosphate buffer wasprepared to serve as a neutral pH control. 1 mL of 2 mM KDG in itssodium salt form was combined with 1 mL of buffer and incubated at 55°C. in an oven for 27 hours. A sample from each reaction was analysed byLC-MS/MS to determine the concentration of HMFA. The results are shownin FIG. 3.

Unlike compounds of formula I, the yield observed on dehydrating KDG toHMFA under mild conditions was no more than 1%, even after 27 hours.

1. A method of preparing a compound of formula II:

where: R₁ and R₂ are independently selected from —CH₂OR′, —CHO, —COOR′and —H, provided that R₁ and R₂ are not both —H; and R′ is selected from—H and C₁₋₆ hydrocarbyl groups, from a compound of formula I:

the compounds of formulas I and II being optionally in the form of asalt, wherein the method comprises dehydrating the compound of formula Iat: a pH in the range of from 0 to 6 or 8 to 11.5; and a temperature inthe range of from 10 to 80° C.
 2. The method of claim 1, wherein thedehydration reaction is carried out at a temperature in the range offrom 15 to 70° C., preferably from 20 to 55° C., and more preferablyfrom 25 to 50° C.
 3. The method of claim 1, wherein the dehydrationreaction is carried out at a pH in the range of from 1.5 to 5,preferably from 1.75 to 4, and more preferably from 2 to 3.5, andpreferably in the presence of an acid selected from: organic acids, suchas from C₁₋₆ carboxylic acids; and inorganic acids, such as fromhydrochloric acid, sulfuric acid, phosphoric acid, nitric acid andhydrobromic acid.
 4. The method of claim 1, wherein the dehydrationreaction is carried out at a pH in the range of from 8.5 to 11.5,preferably from 9 to 11, and more preferably from 9.5 to 10.5, andpreferably in the presence of a base selected from: nitrogen-containingbases (e.g. ammonia, an amine or a nitrogen-containing heterocycle); andmetal-containing bases (e.g. a metal hydroxide, a metal oxide or a metalcarbonate).
 5. The method of claim 1, wherein the dehydration reactionis carried out in the presence of: a heterogeneous, preferablysolid-phase, catalyst; and/or a buffer preferably selected from acitrate buffer, a formate buffer, an acetate buffer, a carbonate buffer,a phosphate buffer, an N-cyclohexyl-2-aminoethanesulfonic acid (CHES)buffer, a borate buffer, a citrate-phosphate buffer, a2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES) buffer,a tris(hydroxymethyl)aminomethane (Tris), 2-(N-morpholino)ethanesulfonicacid (MES) buffer, a sugar acid buffer, or an ammonia buffer.
 6. Themethod of claim 1, wherein the dehydration reaction is carried out inthe presence of a protic solvent, such as water, and preferably whereinthe dehydration reaction is carried out in a solvent system whichcontains water in an amount of at least 50%, preferably at least 70%,and more preferably at least 90% by volume.
 7. The method of claim 1,wherein the dehydration reaction is carried out as a batch process or asa continuous process.
 8. The method of claim 1, wherein the finalconcentration of the compound of formula II in the reaction mixture isgreater than 5 g/L, preferably greater than 10 g/L, and more preferablygreater than 20 g/L of solvent.
 9. The method of claim 1, wherein thecompound of formula II is obtained in a yield of at least 60%,preferably at least 80%, preferably at least 90%, preferably at least95%, preferably at least 99%, and more preferably at least 99.5% yieldfrom formula I.
 10. The method of claim 1, wherein the compounds offormula I and II may be in the form of an alkali metal or alkaline earthmetal salt.
 11. The method of claim 1, wherein the method comprisesproviding the compound of formula I from the following precursor I:

wherein conversion of precursor I into the compound of formula I ispreferably carried out in the presence of an enzyme.
 12. The method ofclaim 11, wherein precursor I is converted into a compound of compoundof formula I, and the compound of formula I is converted into a compoundof formula II, in the same reactor, wherein the pH level in the reactoris preferably selected from: acidic pH levels of from 1.5 to 6,preferably from 2 to 6, and more preferably from 3.5 to 6; and basic pHlevels of from 8 to 11.5, preferably from 8 to 10.5, and more preferablyfrom 8 to 9.5.
 13. The method of claim 1, wherein the method comprisesproviding the compound of formula I from a sugar acid, and the methodpreferably further comprises providing the sugar acid from a sugar. 14.The method of claim 1, wherein R₁ and R₂ are selected from —CH₂OH, —CHO,—COOH and —H, and more preferably from —CH₂OH, —CHO, and —COOH.
 15. Themethod of claim 1, wherein at least one of R₁ and R₂ is selected from—COOH and —CH₂OH, preferably one of R₁ and R₂ is selected from —CH₂OHand the other is selected from —COOH, and more preferably R₁ is —CH₂OHand R₂ is —COOH.
 16. The method of claim 1, wherein both R₁ and R₂ are—COOH.
 17. A method of preparing a compound of formula III:

where: R₄ is selected from —H and —OH; the compound of formula III beingoptionally in the form of a salt, wherein the method comprises:preparing a compound of formula II using the method of claim 1; andprovided that the compounds of formula II and III do not have the samestructure, converting the compound of formula II into a compound offormula III.
 18. The method of claim 17, wherein at least one of R₁ andR₂ in formula II is selected from —CH₂OH, the method comprises oxidisingthe compound of formula II.
 19. A method of preparing a polymercomprising a polymeric unit of formula IV:

wherein the method comprises: preparing a compound of formula III or asalt thereof using a method as defined in claim 17; and forming thepolymer by carrying out a polymerisation reaction using the compound offormula III.
 20. (canceled)